The present invention relates to compounds having inhibiting activity against carnitine palmitoyl transferase. The present invention relates also to pharmaceutical compositions containing at least one of these compounds active ingredients and to the use of said compounds in the preparation of medicaments useful in the treatment of pathologies related to a hyperactivity of carnitine palmitoyl-transferase, in particular hyperglycaemic states, such as diabetes and related pathologies and of congestive heart failure.
To date, hypoglycaemic therapy is based on the use of drugs having different mechanism of action (Arch. Intern. Med., 1997, 157, 1802-1817).
Insulin and its analogues represent the most used therapy, recurring to the direct hypoglycaemic action of this hormone.
Other compounds act indirectly by stimulating insulin release (sulphonylureas). A different target of hypoglycaemic drugs is represented by the reduction of glucose intestinal absorption through the inhibition of intestinal glucosidases, or by reducing insulin resistance.
Hyperglycaemia is also treated with gluconeogenesis inhibitors, such as biguanides.
Some words have also stressed out the relationship between gluconeogenesis and fatty acid oxidation.
The membrane bound long-chain acylcarnitine transferases, also known as carnitine palmitoyltransferase (CPT), are widely represented in organs and subcellular organelles (Bieber, L. L. 1988 Ann. Rev. Biochem. 57: 261-83). The well-established role of this category of enzymes is the transport of activated long-chain fatty acids through mitochondrial membranes. In this context, the outer mitochondrial membrane CIT I catalyzes the formation of long-chain acylcarnitines that are transported across the mitochondrial membrane by a specific carrier, and reconverted into long-chain acyl-coenzyme A esters by CPT II, which resides in the inner mitochondrial membrane. Long-chain acyl-CoAs are then oxidised to acetyl-coenzyme A, which activates a key gluconeogenetic enzyme: pyruvate carboxylase.
Other works report that diabetic patients have high blood levels of fatty acids, whose liver oxidative fate gives rise to an increase of acetyl-coenzyme A, ATP and NADH. High availability of these compounds maximally stimulates gluconeogenesis, which is in part responsible of the elevated glucose blood levels in diabetic patients. CPT inhibition indirectly reduces the extent of liver gluconeogenesis, and hence blood glucose levels.
CPT inhibitors have been disclosed in J. Med. Chem., 1995, 38(18), 3448-50 and in the corresponding European patent application EP 0 574 355 as potential derivatives with hypoglycaemic activity.
Aminocarnitines N-acylated with xe2x80x94COR residue, wherein R is an aliphatic residue with 1 to 19 carbon atoms are disclosed in WO85/04396 useful for investigating the role of transferases in the body, in particular the specificity of carnitine acyltransferase.
Emeriamine and its analogues are disclosed in EP 0 127 098 and J.Med. Chem. 1987, 30, 1458-1463.
Notwithstanding the mechanism of activity above outlined, to date, drugs inhibiting CPT capable to effectively counteract hyperglycaemia do not exist. For some products, such as tetradecyl glycidic acid, or etomoxir, myocardial hypertrophy have been evidenced as side effects (Life Sci., 1989, 44, 1897-1906).
None of the therapies presently used in clinic is fully satisfying, in particular due to the onset of unwanted side effects, such as severe hypoglycaemia, allergic phenomena, oedema, diarrhoea, intestinal disturbances, kidney toxicity, etc.
The necessity to obtain alternative effective therapies for hyperglycaemia still remains.
It has now surprisingly been found that compounds of general formula (I): 
wherein: X+ is selected from the group consisting of N+(R1,R2,R3) and P+(R1,R2,R3), wherein
(R1,R2,R3), being the same or different, are selected in the group consisting of hydrogen and C1-C9 straight or branched alkyl groups, xe2x80x94CHxe2x95x90NH(NH2), xe2x80x94NH2, xe2x80x94OH; or two or more R1, R2 and R3 together with the nitrogen atom, which they are linked to, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic system; with the proviso that at least one of the R1, R2 and R3 is different from hydrogen;
Z is selected from
xe2x80x94OR4,
xe2x80x94OCOOR4,
xe2x80x94OCONHR4,
xe2x80x94OCSNHR4,
xe2x80x94OCSOR4,
xe2x80x94NHR4,
xe2x80x94NHCOR4,
xe2x80x94NHCSR4,
xe2x80x94NHCOOR4,
xe2x80x94NHCSOR4,
xe2x80x94NHCONHR4,
xe2x80x94NHCSNHR4,
xe2x80x94NHSOR4,
xe2x80x94NHSONHR4,
xe2x80x94NHSO2R4,
xe2x80x94NHSO2NHR4,
xe2x80x94SR4,
wherein xe2x80x94R4 is a C1-C20 saturated or unsaturated, straight or branched alkyl group, optionally substituted with a A1 group, wherein A1 is selected from the group consisting of halogen atom, C6-C14 aryl, heteroaryl, aryloxy or heteroaryloxy group, said aryl, heteroaryl, aryloxy or heteroaryloxy groups being optionally substituted with one or more C1-C20 saturated or unsaturated, straight or branched alkyl or alkoxy group and/or halogen atom;
Yxe2x88x92 is selected from the group consisting of xe2x80x94COOxe2x80x94, PO3Hxe2x88x92, xe2x80x94OPO3Hxe2x88x92, tetrazolate-5-yl;
with the proviso that when Z is xe2x80x94NHCOR4, X+ is trimethylammonium, Y is xe2x80x94COOxe2x80x94, then R4 is C20 alkyl;
with the proviso that when Z is xe2x80x94NHSO2R4, X+ is trimethylammonium and Yxe2x88x92 is xe2x80x94COOxe2x80x94, then R4 is not tolyl;
with the proviso that when Z is xe2x80x94NHR4, X+ is trimethylammonium and Yxe2x88x92 is xe2x80x94COOxe2x80x94, then R4 is not C1-C6 alkyl.
The present invention further comprises the use of the compounds of the above-mentioned formula (I) as active ingredients for medicaments, in particular for medicaments useful for the treatment of pathologies related to a hyperactivity of carnitine palmitoyl carnitine, such as and in particular hyperglycemic states, diabetes and related pathologies, congestive heart failure and dilatative cardiopathy.
The present invention comprises pharmaceutical compositions containing compounds of formula (I) as active ingredients, in admixture with pharmaceutically acceptable vehicles and excipients.
The present invention comprises also processes for the preparation of compounds of formula (I).
Within the scope of the present invention, as examples of C1-C20 linear or branched alkyl group, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl and their possible isomers are meant, such as for example isopropyl, isobutyl, tert-butyl.
Examples of C1-C20 linear or branched alkenyl group are methylene, ethylidene, vinyl, allyl, propargyl, butylene, pentylene, wherein the carbon-carbon double bond, optionally in the presence of other carbon-carbon unsaturations, can be situated in the different possible positions of the alkyl chain, which can also be branched within the allowed isomery.
Examples of (C6-C14) aryl group are phenyl, 1- or 2-naphthyl, anthryl, optionally substituted as shown in the general definitions above-mentioned.
Examples of heterocyclic groups thienyl, quinolyl, pyridyl, N-methylpiperidinyl, 5-tetrazolyl, optionally substituted as shown in the general definitions above-mentioned.
As halogen atom it is intended fluorine, chlorine, bromine, iodine.
The compounds of formula (I) can be also in the form of inner salts.
A first group of preferred compounds comprises the compounds of formula (I) wherein N+ (R1,R2,R3) is trimethyl ammonium.
A second group of preferred compounds comprises the compounds of formula (I) wherein two or more R1, R2 and R3, together with the nitrogen atom, which they are linked to, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic system; for example morpholinium, pyridinium, pyrrolidinium, quinolinium, quinuclidinium.
A third group of preferred compounds comprises the compounds of formula (I) wherein R1 and R2 are hydrogen and R3 is selected from the group consisting of xe2x80x94CHxe2x95x90NH(NH2), xe2x80x94NH2 and xe2x80x94OH.
Within the different embodiments of the present invention, the R4 group is preferably a C7-C20 saturated or unsaturated, straight or branched alkyl group. In fact, it has been observed the length of the alkyl chain R4 significantly increases the selectivity against CPT. referred R4 groups are selected from the group consisting of heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl.
Preferred examples of Z group are ureido (xe2x80x94NHCONHR4), and carbamate (xe2x80x94NHCOOR4, xe2x80x94OCONHR4) ones.
In particular, compounds of formula (I) wherein X+, R1, R2, R3, have the above disclosed meanings, Z is ureido (xe2x80x94NHCONHR4) or carbamate (xe2x80x94NHCOOR4, xe2x80x94OCONHR4), R4 is a C7xe2x80x94C20, preferably a C9-C18 saturated or unsaturated, straight or branched alkyl group, are preferred.
The compounds of formula (I) have an asymmetry center on carbon atom bound to a Z group. For the purposes of the present invention, each compound of formula (I) can exist both as R,S racemic mixture and as separated R/S isomeric form.
The compounds of formula (I) are quaternary ammonium or phosphonium derivatives always containing a Yxe2x88x92 anionic group. Dependently on pH, each compounds of formula (I) can exist indifferently as amphoion (inner salt) or as a compound wherein Yxe2x88x92 is present in the YH form. In such a case, X+ is salified with a pharmacologically acceptable acid. Formula (I) covers all these different possibilities. In case of nitrogen atoms having basic character, the salts with pharmaceutically acceptable acids, both inorganic and organic, such as for example, hydrochloric acid, sulfuric acid, acetic acid, or, in the case of acid group, such as carboxyl, the salts with pharmaceutically acceptable bases, both inorganic and organic, such as for example, alkaline and alkaline-earth hydroxides, ammonium hydroxide, amine, also heterocyclic ones. Examples of pharmaceutically acceptable salts are chloride; bromide; iodide; aspartate; acid aspartate; citrate; acid citrate; tartrate; acid tartrate; phosphate, acid phosphate; fumarate; acid fumarate; glycerophosphate; glucosephosphate; lactate; maleate; acid maleate; mucate; orotate; oxalate; acid oxalate; sulfate; acid sulfate; trichloroacetate; trifluoroacetate; methanesulfonate; pamoate and acid pamoate.
A first group of particularly preferred compounds comprises:
R,S-4-trimethylammonium-3-(nonylcarbamoyl)-aminobutyrate;
R,S-4-quinuclidinium-3-(tetradecyloxycarbonyl)-oxybutyrate;
R,S-4-trimethylammonium-3-(nonylcarbamoyl)-oxybutyrate;
R,S-4-trimethylammonium-3-(nonyloxycarbonyl)-oxybutyric acid chloride;
R,S-4-trimethylphosphonium-3-(nonylcarbamoyl)-oxybutyrate;
R,S-4-trimethylammonium-3-(octyloxycarbonyl)-aminobutyrate;
R,S-4-trimethylammonium-3-(nonyloxycarbonyl)-aminobutyrate;
R,S-4-trimethylammonium-3-octyloxybutyrate;
R,S-4-trimethylammonium-3-tetradecyloxybutyrate;
R,S-1-guanidinium-2-tetradecyloxy-3-(tetrazolate-5-yl) -propane;
R,S-1-trimethylammonium-2-tetradecyloxy-3-(tetrazolate-5-yl)-propane;
R,S-3-quinuclidinium-2-(tetradecyloxycarbonyl)-oxy-1-propanephosphonate monobasic;
R,S-3-trimethylammonium-2-(nonylaminocarbonyl)-oxy-1-propanephosphonate monobasic;
R,S-3-pyridinium-2-(nonylaminocarbonyl)-oxy-1-propanephosphonic acid chloride;
R-4-trimethylammonium-3-(tetradecylcarbamoyl)-aminobutyrate;
R-4-trimethylammonium-3-(undecylcarbamoyl) -aminobutyrate;
R-4-trimethylammonium-3-(heptylcarbamoyl)-aminobutyrate;
R-4-trimethylammonium-3-(nonylthicarbamoyl)-aminobutyrate;
R,S-4-trimethylammonium-3-(nonylthiocarbamoyl)-aminobutyrate;
R-4-trimethylammonium-3-(nonylcarbamoyl)-aminobutyrate;
S-4-trimethylammonium-3-(nonylcarbamoyl)-aminobutyrate;
S-4-trimethylammonium-3-(tetradecylcarbamoyl)-aminobutyrate;
R,S-4-trimethylammonium-3 -tetradecylaminobutyrate;
R,S-4-trimethylammonium-3-octylaminobutyrate;
R,S-4-trimethylammonium-3-(decansulfonyl)aminobutyrate;
R,S-4-trimethylammonium-3-(nonylsulfamoyl)aminobutyrate;
S-4-trimethylammonium-3-(dodecansulfonyl)aminobutyrate;
R-4-trimethylammonium-3-(dodecansulfonyl)aminobutyrate;
S-4-trimethylammonium-3-(undecylsulfamoyl)aminobutyrate;
R-4-trimethylammonium-3-(undecylsulfamoyl)aminobutyrate;
R-4-trimethylammonium-3-(dodecylcarbamoyl)aninobutyrate;
R-4-trimethylammonium-3-(10-phenoxydecylcarbamoyl)aminobutyrate;
R-4-trimethylammonium-3-(trans-xcex2-styrenesulfonyl)aminobutyrate.
The compounds of formula (I) can be prepared with reactions that are well known in the state of the art. A process for the preparation of the compounds of claim 1, wherein Z is xe2x80x94NHR4 comprising the reaction of X+xe2x80x94CH2xe2x80x94CH(NH2)xe2x80x94CH2xe2x80x94Yxe2x88x92, wherein X+ and Yxe2x88x92 have the same meanings as in claim 1, of the desired structure, optionally protected on the acid Yxe2x88x92 group, with alkane carbaldheydes, wherein the alkyl moiety is a one-term lower homologue of the desired R4, and subsequent reduction.
Generally, the compounds of formula (I), wherein Z is carbonate (xe2x80x94OCOOR4), carbamate (xe2x80x94OCONHR4, xe2x80x94NHCOOR4), thiocarbamate (xe2x80x94OCSNHR4, xe2x80x94NHCSOR4,) or thiocarbonate (xe2x80x94OCSOR4), are obtained by reacting a compound of formula X+xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94Yxe2x88x92, wherein X+ and Yxe2x88x92 are as above defined, of the desired structure, optionally protected on the acid Yxe2x88x92 group, respectively with alkyl chloroformates, alkyl isocyanates, alkyl isothiocyanates, alkyl thiochloroformates, containing the desired R4 alkyl group.
Compounds of formula (I), wherein Z is amide (xe2x80x94NHCOR4), thioamide (xe2x80x94NHCSR4), carbamate (xe2x80x94NHCOOR4, xe2x80x94OCONHR4), thiocarbamate (xe2x80x94NHCSOR4, xe2x80x94OCSNHR4,), ureido (xe2x80x94NHCONHR4), thioureido (xe2x80x94NHCSNHR4), sulfinamide (xe2x80x94NHSOR4), sulfonamide (xe2x80x94NHSO2R4), sulfinamoylamino (xe2x80x94NHSONHR4), and sulfamide (xe2x80x94NHSO2NHR4), are obtained by reacting X+xe2x80x94CH2xe2x80x94CH(NH2)xe2x80x94CH2xe2x80x94Yxe2x80x94, wherein X+ and Yxe2x88x92 are as above defined, of the desired structure, optionally protected on the acid Yxe2x88x92 group, respectively with acyl chlorides, thioacyl chlorides, alkyl chloroformates, alkyl thiochloroformates, alkyl isocyanates, alkyl thioisocyanates, alkyl sulfinyl chlorides, alkyl sulfonyl chlorides, SOCl2 and alkyl amines, alkyl sulfamoyl chlorides (or SO2Cl2 and alkyl amines), containing the desired R4 alkyl group.
Compounds of formula (I), wherein Z is xe2x80x94OR4 or xe2x80x94SR4 are obtained by the reaction of carbonyl compounds of formula Hal-CH2xe2x80x94COxe2x80x94CH2xe2x80x94COORxe2x80x2, wherein Hal is a halogen atom, preferably chlorine, and Rxe2x80x2 is the residue of a suitable ester, such as for example a lower alkyl ester (an ethyl or a tert-butyl ester) with respectively alcohols and thiols R4OH or R4SH, wherein R4 is as above defined, to give the respective ketal or thioketal, followed by the transformation of the respective ketal or thioketal into the respective ether or thioether, subsequent substitution of the Hal atom with a nucleophilic group, such as azido, phthalimido, nitro, amino, alkyl amino group, and transformation of the nucleophilic group into the X+ group, wherein X+ is N+(R1,R2,R3) or, alternatively the Hal atom is substituted with a (R1,R2,R3)-substituted phosphine to obtain the compounds of formula (I) wherein X+ is P+(R1,R2,R3).
Compounds of formula (I), wherein Z is xe2x80x94NHR4 are obtained by reacting X+xe2x80x94CH2xe2x80x94CH(NH2)xe2x80x94CH2xe2x80x94Yxe2x88x92, wherein X+ and Yxe2x88x92 have the same meanings as in claim 1, of the desired structure, optionally protected on the acid Yxe2x88x92 group, with alkane carbaldheydes, wherein the alkyl moiety is a one-term lower homologue of R4 and subsequent reduction.
Regarding the various meanings of R4, present in the different reactives, these reactives are available in the market, or can be prepared according to well-known methods in literature, which the experts in the field can resort to, completing with their own knowledge of the argument.
Pharmaceutically acceptable salts are obtained with conventional methods found in the literature, and do not necessitate of further disclosure.
The compounds disclosed in the present invention have reversible inhibiting activity of carnitine palmitoyl-transferase (CPT). This activity allows their use as active ingredients in the preparation of medicaments useful for the treatment and prevention of hyperglycaemia, diabetes and disorders related thereto, such as, for example diabetic retinopathy, diabetic neuropathy. The compounds of the present invention are also useful as active ingredient for the treatment and prevention of cardiovascular disorders, such as congestive heart failure. The compounds of formula (I) are also applicable for medicaments for the prevention and treatment of ketonic states, wherein it is intended the pathological conditions characterized by high levels of ketone bodies in blood.
Inhibiting activity mainly occurs on the isoform I of palmitoyl carnitine transferase (CPT-I).
A further object of the present invention relates to pharmaceutical compositions comprising at least a compound of formula (I), in an amount such as to produce a significant therapeutical effect. The compositions according to the present invention are conventional and are obtained with commonly used methods in the pharmaceutical industry. According to the desired administration route, the compositions shall be in solid or liquid form, suitable to the oral, parenteral, intravenous or transdermal route. The compositions according to the present invention comprise together with the active ingredients at least a pharmaceutically acceptable vehicle or excipient. Formulation co-adjuvants, for example solubilizing, dispersing, suspending, emulsionating agents can be particularly useful. Examples of suitable oral pharmaceutical compositions are capsules, tablets, granulates, powders, syrups, elixirs. Examples of suitable parenteral pharmaceutical compositions are solutions, emulsions, suspensions. Examples of suitable transdermal pharmaceutical compositions are patches, subcutaneous implants.
The compounds of formula (I) can also be used in combination with other well-known active ingredients.
The dose of the active ingredients will vary depending on the kind of active ingredient used, the administration route, the grade of pathology to be treated and the general conditions of the subject. The dosage and posology shall be determined by the clinic expert or the physician. Generally, a therapeutic effect can be obtained at dosages comprised between 1 and 100 mg/kg body weight.
The compounds according to the present invention are useful as medicaments with hypoglycaemic activity. A further object of the present invention is the preparation of a pharmaceutical composition comprising admixing at least a compound of formula (I) with suitable pharmaceutically acceptable excipients and/ or vehicles.